Analysis of single nucleotide polymorphisms (SNPs) to assess the genetic risk of disease

An approach to elucidate the genetic basis of human complex diseases and to identify the possible genetic risk factors, is to analyze the distribution of single nucleotide polymorphisms (SNPs) in affected and control populations and assess the genetic risk of disease. Four genetic association studies were reported in this work that attempt to determine clinical significance of several genetic variants in the development and progression of complex human diseases, such as gastric cancer, lymphoma and systemic sclerosis. In the first study, two polymorphisms in the ADP-ribosylation factor-like tumorsuppressor gene 1 (ARLTS1) gene, already reported to be predisposing for various types of familial cancers, were associated with risk of gastric cancer. We analyzed the frequency of G446A and T442C polymorphisms in a series of 297 patients and 340 controls, by means of direct sequencing, and we found significant differences in the frequencies between the two groups. These results suggest that ARLTS1 may be related to the pathogenesis of gastric cancer. Polymorphisms in several genes involved in an inflammatory response have been variably associated with increased risk for development of gastric cancer. We have examined the genotypic frequencies of 10 polymorphisms in the inflammatory genes IL1A, IL1B, IL1RN, IL2, IL6, IL10, TNF, and LTA in 453 patients with gastric cancer and 1174 controls. Cancers included 328 intestinal, 99 diffuse and 26 mixed histotype. We found no statistically significant correlations between the risk of gastric cancer and the IL1B-31 and IL1B-511 alleles. Of the remainder of the polymorphisms, only the IL10- 3575 SNP showed a significantly different distribution between cases and controls. Geographical differences attributable to diet, lifestyles or genetic background may be potential sources of discrepant results among previous reports. Our data do not support an association between polymorphisms in IL1B and an increased risk for gastric cancer, but instead, suggest that variants in the IL10 gene may confer increased risk. Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more SNPs were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls. The TNF G- 308A and IL10 T−3575A polymorphisms were associated with increased risk of non- Hodgkin lymphoma, particularly for diffuse large B-cell lymphoma, the main histological subtype, but not for follicular lymphoma. For individuals homozygous for the TNF −308A allele and carrying at least one IL10 −3575A allele, risk of diffuse large B-cell lymphoma doubled. These results suggest that common polymorphisms in TNF and IL10, which are key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. The last genetic association study reported in this work aims to investigate possible associations of 9 single nucleotide polymorphisms in the IL10, IL1B, IL1A, IL1RN, IL2, LTA and IL6 genes with susceptibility to rare autoimmune disease, systemic sclerosis (SSc). A total of 78 patients with SSc [diffuse SSc (dcSSc), n=31; limited SSc, (lcSSc), n=47] and 692 healthy blood donors were genotyped. Alleles in IL1B-31 and IL1B-511 showed a significantly different distribution between cases and controls. Carriers of at least one copy of the IL1B-31-C allele had an increased risk of SSc, while a similar strong association was also evident for IL1B-511-T carriers. Interestingly, carriers of the IL2- 384-G allele were significantly more frequent in lcSSc patients, compared to patients with the diffuse subtype. Lastly, the distribution of the IL2-384 genotype showed statistically significant differences between controls and lcSSc patients. There were no differences between dcSSc patients and controls. We concluded that IL1B and IL2 gene polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele may be a marker for the limited phenotype of SSc.